Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure.

PURPOSE: Nonconvulsive status epilepticus is an unusual complication of cephalosporin therapy, with only a few isolated cases reported. SUBJECTS AND METHODS: We reviewed the clinical and electroencephalographic (EEG) characteristics of 10 patients with renal failure in whom developed alteration of consciousness without convulsions associated with continuous epileptiform EEG activity while being treated with cephalosporins. RESULTS: Nonconvulsive status epilepticus developed in 5 men and 5 women, with a mean (+/- SD) age of 69 +/- 14 years, while receiving intravenous cephalosporins (ceftriaxone, 2 patients; ceftazidime, 2; and cefepime, 6). All patients had renal failure; 1 also had hepatic failure. Patients presented with progressive disorientation or agitation, sometimes associated with mild facial or limb myoclonus, that had begun 1 to 10 days (mean, 5 +/- 2 days) after starting cephalosporin treatment. The EEG showed continuous or intermittent bursts of generalized, high-voltage, 1 to 2 Hz sharp wave activity or sharp and slow wave activity that resembled, but could be differentiated from, the triphasic waves seen in metabolic encephalopathies. Intravenous clonazepam suppressed the epileptiform activity completely in 5 patients and partially in the other 5. Cephalosporins were withdrawn, and antiepileptic therapy was started for all patients. All patients improved, 2 in less than 24 hours and the remainder within 2 to 7 days. CONCLUSIONS: Cephalosporins can cause nonconvulsive status epilepticus in patients with renal failure. The clinical picture is difficult to differentiate from a that of metabolic encephalopathy unless an EEG is obtained. Physicians should be aware of this potentially dangerous complication.

Unintegrated HIV-1 circular 2-LTR proviral DNA as a marker of recently infected cells: relative effect of recombinant CD4, zidovudine, and saquinavir in vitro.

Unintegrated HIV-1 proviral DNA is one of the earliest detectable forms of HIV-1, and the influence of an antiretroviral drug on its appearance may reflect the efficacy of that agent in preventing infection of new cells. We characterized the dynamics of HIV-1 p24 (p24) antigen production, HIV-1 gag DNA, tandem long-terminal-repeat circular unintegrated proviral (2-LTR) HIV-1 DNA, HIV-1 tat mRNA, and cell viability in the presence of three antiretroviral agents: recombinant soluble CD4 (rsCD4), zidovudine, and saquinavir. Interference with HIV-1 entry by rsCD4 decreased p24 antigen levels modestly, decreased HIV-1 gag by twofold, and 2-LTR was detectable at the end of the culture period. Inhibition of reverse transcription by zidovudine decreased p24 antigen levels modestly, decreased HIV-1 gag by 19-fold, and inhibited detection of 2-LTR HIV-1 DNA. The protease inhibitor, saquinavir, had the greatest overall effect, with the lowest levels of p24 antigen and HIV-1 gag, and inhibition of 2-LTR. There was no detection of tat mRNA in the saquinavir-treated cultures. In addition, cell viability was significantly higher in cultures treated with saquinavir. In these experiments, 2-LTR HIV-1 DNA was indicative of the relative inhibitory effects of three antiretroviral agents acting at different steps of the HIV-1 replication cycle. We demonstrated in vitro that 2-LTR HIV-1 DNA was a useful indicator of an antiretroviral drug in preventing new cell infection and could be utilized as a dynamic marker of drug efficacy in HIV-1-infected patients.

Hepatitis G virus co-infection does not alter the course of recurrent hepatitis C virus infection in liver transplantation recipients.

Although hepatitis G virus infection (HGV) is usually asymptomatic, it has been associated with mild hepatic injury. Whether hepatitis G co-infection alters the natural history of other viral hepatitis infections remains to be determined. In the present study, we investigated whether hepatitis G impacts on the time to recurrent hepatitis or on the time to progression to fibrosis in hepatitis C-infected patients who undergo liver transplantation. Forty-five liver transplantation recipients with persistent hepatitis C viremia by polymerase chain reaction (PCR) were evaluated. Stored sera obtained before and after liver transplantation was tested for HGV RNA by reverse transcriptase (RT)-PCR using primers to the 5' region of the HGV genome. A median of eight serial liver biopsy specimens were reviewed per patient. The prevalence of HGV co-infection was 21% before transplantation and 22% following transplantation. During a median follow-up of 29 months, 78% (35/45) of patients with hepatitis C viremia developed histological features of recurrent hepatitis. Fifty-one percent (23/45) progressed to fibrous portal expansion and 16% (7/45) developed bridging fibrosis. Comparisons of patients with and without hepatitis G co-infection following transplantation showed no significant difference in time to recurrent hepatitis, fibrous portal expansion, bridging fibrosis, or of allograft or patient survival. In conclusion, hepatitis G co-infection does not seem to impact on the time to recurrent hepatitis C or progression of hepatitis C-related histological injury after liver transplantation.

Assessment of hepatitis C viremia using molecular amplification technologies: correlations and clinical implications.

OBJECTIVE: To compare two recently developed molecular techniques for quantitating the levels of hepatitis C virus (HCV) RNA in the serum of patients with a wide spectrum of chronic hepatitis C. DESIGN: Serum samples from 299 patients with HCV viremia, 101 control patients without HCV infection, and 19 consecutive patients receiving systemic interferon therapy were evaluated by a commercially available branched-chain DNA (bDNA) assay and a quantitative competitive polymerase chain reaction (PCR). SETTING: University-based hepatology clinics and reference virology laboratory. PATIENTS: Patients with HCV viremia as defined by results of qualitative RNA PCR, including 53 HCV-infected blood donors, 34 patients receiving renal dialysis, and 212 patients attending a hepatology clinic. RESULTS: Results of in vitro and in vivo experiments indicated that the sensitivity and dynamic range of the PCR assays were greater than those of the bDNA assay. Detection of HCV viremia by the bDNA assay was highly dependent on viral RNA titers, with a sensitivity of 5% at HCV RNA titers of 5.0 logs per mL or less and 94% at titers of 5.5 logs per mL or greater. The best correlation between assays was observed in specimens with HCV RNA titers between 6.0 and 7.5 logs per mL (r = 0.73). In patients with high-titer HCV viremia, including liver transplant recipients and patients with cirrhosis, quantitative PCR results were an average of 12-fold higher than bDNA assay results. Results of repetitive testing of discordant specimens showed that these discrepancies were caused by a high kit-to-kit coefficient of variation (112%) in the bDNA assay. Of 19 patients receiving interferon therapy, 9 (47%) became bDNA negative, but only 5 became quantitative PCR negative. The bDNA-negative, quantitative PCR-positive patients all had relapse when therapy was discontinued. CONCLUSIONS: The bDNA assay has a narrower linear range for quantitation of HCV viremia than quantitative PCR. Because persons with low HCV titers may respond well to therapy, seropositive persons with negative bDNA results should be retested with PCR-based assays. Similarly, the bDNA assay may underestimate the true degree of HCV viremia in persons with end-stage infection (> 10(7) RNA equivalents/mL of sera). Despite these limitations, the combination of bDNA- and PCR-based assays appears to be optimal for selecting and following patients during interferon therapy.

Persistent hepatitis C virus infection after liver transplantation: clinical and virological features.

We report a prospective clinical and virological study of 18 patients undergoing orthotopic liver transplantation, selected because of hepatitis C virus (HCV) RNA positivity before transplantation. Nine of the 18 patients (50%) developed chronic active hepatitis (CAH) in liver allografts during the first year posttransplantation; hepatitis was first observed between 6 and 25 weeks posttransplantation. HCV viremia was measured for all patients before transplantation and on posttransplantation days 3, 7, and 14, and months 1, 6, 12, and 24 to 41, by quantitative competitive RNA polymerase chain reaction (QC-PCR). HCV RNA levels on posttransplantation days 3, 7, and 14 were significantly higher among patients who subsequently developed CAH versus those who did not (P < .02 by t-test and Mann-Whitney test on all three dates). However, HCV RNA levels in sera obtained at 1, 6, and 12 months posttransplantation did not correlate with CAH at 1 year or with HCV genotype determined in posttransplantation sera. At least two serial liver biopsy specimens from each patient were stained for HCV nonstructural 4 (NS4) antigen by immunohistochemistry. The intensity of cytoplasmic staining of NS4 antigen was significantly higher for specimens with CAH versus those without CAH (P = .028 by chi 2). Three patients developed bridging fibrosis in liver allografts during the first year after transplantation; all three patients had intense (3+) immunostaining for NS4 antigen, and the infecting genotypes were 1a, 1b, and 1a plus 1b, respectively. In summary, the 18 patients all developed high-titer viremia by 1 month after liver transplantation, whereas CAH developed in 50% of allografts during the first year after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatitis C--associated glomerular disease in liver transplant recipients.

Hepatitis C virus (HCV) infection may be associated with extrahepatic illness including renal disease. We investigated the clinical and virological characteristics of three patients who developed a mesangial proliferative and sclerosing glomerulopathy alone or in association with membranoproliferative glomerulonephritis after liver transplantation for end-stage liver disease secondary to HCV infection. Using polymerase chain reaction technology and the IgM RIBA assay, viral load, genotype and IgM antibody response to HCV in the setting of glomerulonephritis was evaluated. Within 1 year of transplantation, the patients showed decreased renal function, proteinuria and recurrent hepatitis C liver disease. Likewise, HCV viral load increased following transplantation, whereas the viral genotypes remained unchanged. Although the first patient presented with classic type II cryoglobulinemia in association with glomerulonephritis, the second patient developed an IgM directed specifically against the hepatitis C core antigen. The third patient developed a low-titered IgM directed against the hepatitis C core antigen with rheumatoid factor activity but without cryoglobulinemia. All of the patients show IgM in glomerular capillary walls by biopsy. One patient has shown a clinical response to interferon (IFN) alfa-2b therapy without evidence of hepatic allograft rejection. The second and third patients have not responded to IFN or developed hepatic rejection. This study suggests that HCV-associated glomerulonephritis may complicate liver transplantation in conjunction with the production of increased amounts of IgM of variable specificity. The posttransplant setting may provide a unique situation in which to investigate the specific requirements for the onset of renal disease.

Quantitation of hepatitis C viral RNA in sera of hemodialysis patients: gender-related differences in viral load.

Hepatitis C virus (HCV) infection is common in hemodialysis patients, as determined by antibody assays and qualitative polymerase chain reaction (PCR) analysis of serum HCV RNA. To further characterize HCV infection in this population, we measured the viral load in infected hemodialysis patients by a quantitative, competitive PCR assay (QC-PCR) for HCV RNA. Hepatitis C virus RNA levels were correlated with serologic, biochemical, and demographic features of a cohort of hemodialysis patients. Sera from 208 hemodialysis patients were screened for HCV RNA (5' conserved region) by reverse transcriptase PCR (RT-PCR) and HCV-specific antibody. Forty-four patients were antibody positive (21%); among these patients, 34 (77%) were HCV RNA positive. No viremic, seronegative patients were identified. Hepatitis C virus RNA levels quantitated by QC-PCR ranged from 3 x 10(5) to 10(8) molecules of HCV RNA/mL. Male patients had significantly higher mean and median HCV RNA levels (10(7) molecules/mL) compared with female patients (3.6 x 10(6) molecules/mL and 3 x 10(6) molecules/mL, respectfully; P = 0.02). No other demographic or clinical feature of this cohort correlated with HCV RNA levels. Intravenous drug abuse was the most frequently identified risk factor (29% of seropositive patients) for infection with HCV in this population. No association between HCV RNA levels and hepatic enzyme levels (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase) was apparent. Hepatitis C virus infection is highly prevalent in our hemodialysis population, and hemodialysis patients, particularly males, have high levels of HCV in serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of hepatitis C virus RNA levels by quantitative competitive RNA polymerase chain reaction: high-titer viremia correlates with advanced stage of disease.

A quantitative competitive RNA polymerase chain reaction (QC-PCR) assay was developed for measuring absolute levels of hepatitis C virus (HCV) RNA in the sera of 121 viremic persons, including 64 asymptomatic blood donors, 39 symptomatic patients referred for treatment of chronic hepatitis C, and 18 patients with end-stage liver disease referred for liver transplantation. Mean HCV RNA levels (log molecules per milliliter) were lowest among blood donors with normal alanine aminotransferase (ALT) values (5.8 +/- 1.5), higher among blood donors with elevated ALT (6.9 +/- 0.8) and clinic patients with chronic active hepatitis (6.9 +/- 0.7), and highest among patients with cirrhosis (7.1 +/- 0.8) or end-stage liver disease (7.6 +/- 1.0). High-titer viremia ( > or = 7.5 logs/mL) was more frequent among patients with end-stage liver disease (14/18; 78%) than either blood donors (10/64; P < .001) or patients with chronic active hepatitis (7/26; P < .001). Thus, 121 (94.5%) of 128 anti-HCV-positive persons were viremic. QC-PCR may be valuable for monitoring HCV infection status and selecting individuals for therapy.

Detection of hepatitis C virus RNA: comparison of one-stage polymerase chain reaction (PCR) with nested-set PCR.

We evaluated a new hepatitis C virus RNA assay based on one-stage PCR followed by liquid hybridization with an oligonucleotide probe and compared it with nested-set PCR. The one-stage and nested-set PCR assays had identical sensitivities in analytical experiments and showed 100% concordance when clinical specimens were used. One-stage PCR may be less prone to contamination than nested-set PCR.